Postdoctoral Fellow The University of Hong Kong, United States
Abstract: Zika virus (ZIKV) has emerged as a significant global health threat in recent years. However, there are currently no approved antiviral drugs or vaccine available for the treatment or prevention of Zika virus infection. The programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling pathway is known to inhibit immune responses against cancers and regulate antiviral immune responses modulated by various viruses. However, its role in ZIKV infection remains unclear. Our study revealed that ZIKV infection upregulates mRNA and protein expression of PD-L1 in SF268 and JEG3 cell lines, as well as human dendritic cells. Furthermore, it is noteworthy that ZIKV infection also enhances PD-L1 expression in human trophoblast stem cells (hTSCs). Screening viral proteins, we identified NS4B as the primary viral protein inducing PD-L1 expression and promoter activities in a dose-dependent manner. In C57BL/6 mice, elevated PD-L1 expression was observed in the brain, testis, and spleen post-infection. Notably, ZIKV infection elevated antigen-specific CD8+ T cells and PD-1+ CD8+ T cells. Blocking PD-L1 effectively inhibited ZIKV infection, reducing virus load in the brain, testis, and spleen of A129 mice. Furthermore, anti-PD-L1 antibody treatment further increased virus-specific CD8+ T cells, KLRG+ CD8+ T cells, and memory CD8+ T cells. PD-L1 blockade also enhanced IFN-gamma, granzyme B, and IL-2 expression in antigen-specific CD8 T cells, indicating improved T cell functionality. These findings suggest that targeting the PD-1/PD-L1 pathway could be a promising immunotherapy strategy against ZIKV infection.
